Referring to FIG. 1, the nasal airway 1 comprises the two nasal cavities separated by the nasal septum, which airway 1 includes numerous ostia, such as the paranasal sinus ostia 3 and the tubal ostia 5, and olfactory cells, and is lined by the nasal mucosa. The nasal airway 1 can communicate with the nasopharynx 7, the oral cavity 9 and the lower airway 11, with the nasal airway 1 being in selective communication with the anterior region of the nasopharynx 7 and the oral cavity 9 by opening and closing of the oropharyngeal velum 13. The velum 13, which is often referred to as the soft palate, is illustrated in solid line in the closed position, as achieved by providing a certain positive pressure in the oral cavity 9, such as achieved on exhalation through the oral cavity 9, and in dashed line in the open position.
There are many nasal conditions which require treatment. One such condition is nasal inflammation, specifically rhinitis, which can be allergic or non-allergic and is often associated with infection and prevents normal nasal function. By way of example, allergic and non-allergic inflammation of the nasal airway can typically effect between 10 and 20% of the population, with nasal congestion of the erectile tissues of the nasal concha, lacrimation, secretion of watery mucus, sneezing and itching being the most common symptoms. As will be understood, nasal congestion impedes nasal breathing and promotes oral breathing, leading to snoring and sleep disturbance. Other nasal conditions include nasal polyps which arise from the paranasal sinuses, hypertrophic adenoids, secretory otitis media, sinus disease and reduced olfaction.
In the treatment of certain nasal conditions, the topical administration of medicaments is preferable, particularly where the nasal mucosa is the prime pathological pathway, such as in treating or relieving nasal congestion. Medicaments that are commonly topically delivered include decongestants, anti-histamines, cromoglycates, steroids and antibiotics. At present, among the known anti-inflammatory pharmaceuticals, topical steroids have been shown to have an effect on nasal congestion. Topical decongestants have also been suggested for use in relieving nasal congestion. The treatment of hypertrophic adenoids and chronic secretory otitis media using topical decongestants, steroids and anti-microbial agents, although somewhat controversial, has also been proposed. Further, the topical administration of pharmaceuticals has been used to treat or at least relieve symptoms of inflammation in the anterior region of the nasopharynx, the paranasal sinuses and the auditory tubes.
Medicaments can also be systemically delivered through the nasal pathway, the nasal pathway offering a good administration route for the systemic delivery of pharmaceuticals, such as hormones, for example, oxytocin and calcitionin, and analgetics, such as anti-migraine compositions, as the high blood flow and large surface area of the nasal mucosa advantageously provides for rapid systemic uptake.
Nasal delivery is also expected to be advantageous for the administration of medicaments requiring a rapid onset of action, for example, analgetics, anti-emetics, insulin, anti-epileptics, sedatives and hypnotica, and other pharmaceuticals, for example, cardio-vascular drugs. It is envisaged that nasal administration will provide for a fast onset of action, at a rate similar to that of injection and at a rate much faster than that of oral administration. Indeed, for the treatment of many acute conditions, nasal administration is advantageous over oral administration, since gastric stasis can further slow the onset of action following oral administration.
It is also expected that nasal delivery could provide an effective delivery route for the administration of proteins and peptides as produced by modern biotechnological techniques. For such substances, the metabolism in the intestines and the first-pass-effect in the liver represent significant obstacles for reliable and cost-efficiency delivery. Furthermore, it is expected that nasal delivery using the nasal delivery technique of the present invention will prove effective in the treatment of many common neurological diseases, such as Alzheimer's, Parkinson's, psychiatric diseases and intracerebral infections, where not possible using existing techniques. The nasal delivery technique of the present invention allows for delivery to the olfactory region, which region is located in the superior region of the nasal cavities and represents the only region where it is possible to circumvent the blood-to-brain barrier (BBB) and enable communication with the cerebrospinal fluid (CSF) and the brain.
Also, it is expected that the nasal delivery technique of the present invention will allow for the effective delivery of vaccines.
Aside from the delivery of medicaments, the irrigation of the nasal mucosa with liquids, in particular saline solutions, is commonly practised to remove particles and secretions, as well as to improve the mucociliary activity of the nasal mucosa. These solutions can be used in combination with active pharmaceuticals.
For any kind of drug delivery, accurate and reliable dosing is essential, but it is of particular importance in relation to the administration of potent drugs which have a narrow therapeutic window, drugs with potentially serious adverse affects and drugs for the treatment of serious and life-threatening conditions. For some conditions, it is essential to individualize the dosage to the particular situation, for example, in the case of diabetes mellitus. For diabetes, and, indeed, for many other conditions, the dosage of the pharmaceutical is preferably based on actual real-time measurements. Currently, blood samples are most frequently used, but the analysis of molecules in the exhalation breath of subjects has been proposed as an alternative to blood analysis for several conditions. Breath analysis is currently used for the diagnosis of conditions such as helicobacter pylon infections which cause gastric ulcers.
To date, nasal medicaments have been primarily delivered as drops or by mechanical nasal spray pumps. With mechanical spray pumps, the mean particle size is typically between 40 μm and 80 μm in order to prevent the inhalation of delivered particles. In general, particles smaller than 10 μm will bypass the nose and can be inhaled. Indeed, the new FDA guidelines require that the fraction of particles less than 10 μm be at most 5%.
Whilst the provision of a spray having a larger mean particle size prevents the inhalation of the particles, these larger particles are not optimal for achieving a good distribution to the nasal mucosa.
The applicant has now recognized that the closure of the oropharyngeal velum during the delivery of a substance to the nasal airway prevents the possible inhalation of the substance, thereby enabling the delivery of an aerosol having a much smaller mean particle size than achieved by traditional nasal spray pumps. In this way, an aerosol can be generated which has an optimal particle size distribution.
A further advantage is that the nosepiece acts to expand the narrowest, anterior part of the nasal cavity and thereby reduces the unwanted high deposition in the anterior region of the nasal cavity which is lined by squamous epithelium.
In addition, the applicant has recognized that, by establishing a bidirectional flow through the nasal cavities as described in WO-A-00/51672, that is, an air flow which passes into one nostril, around the posterior margin of the nasal septum and in the opposite direction out of the other nostril, an aerosol having an optimal flow rate and timing can be generated. Furthermore, the bidirectional air flow advantageously acts to stimulate the sensory nerves in the nasal mucosa, thereby conditioning the subject for the delivery and providing a more comfortable delivery situation.
A yet further advantage is that the air flow acts to create a positive pressure inside the nasal passages connected in series, which tends to expand and widen narrow and congested regions.
A still yet further advantage is that the two-point fixation of the device in the nose with a well-fitting nozzle and in the mouth provides a much more stable and reproducible positioning of the device as compared to traditional spray pumps. Thus, in addition to improved deposition and reproducibility, the new concept provides a more user-friendly and intuitive nasal delivery method.
Furthermore, the delivery device, in being pre-primed and actuatable by the oral exhalation breath of a subject, does not require the application of an actuation force by the subject at the time of actuation. Traditionally, mechanical liquid delivery pumps are operated by the manual compression of a chamber containing a volume of liquid to expel a flow of a metered volume of liquid, and mechanical powder delivery pumps are operated by the manual compression of a chamber containing a volume of air to drive and expel a flow of a metered amount of a dry powder. Such operation requires a relatively high actuation force, typically of the order of 50 N, which high force often leads to significant movement of the delivery device, it being very difficult to maintain a delivery device stationary when attempting to apply a high actuation force. Movement of the delivery device, both in the positioning and orientation of the nozzle, will lead to poor reproducibility, dose accuracy and patient compliance. In being pre-primed and actuatable by the oral exhalation breath of a subject, the delivery device of the present invention overcomes this problem.
In addition, by not requiring a subject to apply an actuation force at the instance of delivery, the delivery device provides for the same actuation force in each delivery, and also provides for delivery at an optimal pressure and/or flow rate, and the delivery of substance having an optimized particle size distribution.
Yet furthermore, in providing for the closure of the oropharyngeal velum of a subject, substance is prevented from entering the lower airway, and also, in a preferred embodiment, bi-directional delivery can be achieved through the nasal cavities.
It will be appreciated that the nasal delivery devices of the present invention are quite different to inhalation devices which provide for inhalation into the lower airway.
Inhalation devices have been used for a long time for the inhalation of medicaments in the treatment of lower airway pathologies.
One such inhalation device is the pressurized metered dose inhaler (pMDI). In such inhalers, a metered dose of medicament is released as an aerosol by actuating an aerosol canister, with the particle sizes of the aerosol being required to be small, typically less than 5 μm, in order to reach the distal parts of the lower airway. One drawback with traditional pMDIs is that the subject must co-ordinate inhalation with the aerosol release in order to deliver the aerosolized medicament effectively to the lower airway. Inadequate co-ordination represents a considerable problem, significantly reducing both lung deposition and reproducibility. Another drawback with traditional pMDIs is the use of chlorine-containing compounds as the propellant gas, as such gases are not environmentally friendly and have been demonstrated to destroy the ozone layer. Recently, in order to alleviate these drawbacks, pMDIs have been developed which use an alternative propellant gas, this being a hydrofluoroalkane (HFA), and incorporate a breath-actuation mechanism which provides for actuation of the aerosol canister on inhalation by the subject.
Another such inhalation device is the dry powder inhaler, such as the Turbohaler® inhaler as supplied by AstraZeneca and the Discus® inhaler as supplied by GSK. These dry powder inhalers do not require co-ordination of delivery and inhalation and can improve deposition to the lower airways.
Bi-directional nasal drug delivery is achieved by directing an exhaled air flow through the nasal passages in series, or by triggering another flow source to create such an air flow, whereas breath actuation of pulmonary drug delivery is by inhalation into a closed expanding volume, that is, the lungs. For bi-directional nasal delivery, it is desirable to establish the air flow before the drug is released, whereas for inhalation, the release is best achieved at the very beginning of inspiration to reach the most distal parts of the lungs.
Increased airway resistance in pathological conditions, both in the pulmonary and nasal airways, is a challenge. In inhalation devices, an air flow is created by the inspiratory muscles creating a negative pressure inside the chest. In this way, air is sucked through the device and into the airways. For pulmonary drug delivery, it is essential that the triggering occurs, not only early, but also at a relatively low flow to ensure release in subjects with a very low lung capacity. Furthermore, the releasing action should require as little energy as possible, as any resistance in the device will impede free inhalation. Still most subjects, even patients with lung diseases, will be able to achieve a flow rate of 25 L/min which is typically required to trigger the release from a pMDI device.
For the nose, the situation is more complex and in many ways different. The expiratory muscles in the thorax produce the exhaled air flow used to trigger release, and this air flow is then directed through the device and into the nasal passages in series, or used to trigger another flow source. Thus, the triggering air flow is completely reversed as compared to pulmonary breath actuation, and the air flow is directed into another airway/compartment separated from the lower airways.
Furthermore, the nose geometry is designed to humidify, warm and filter the inspired air to protect the lower airways. The resistance in the nose alone equals 50% of the total airway resistance, and the resistance may increase immensely when congested. Owing to the high anterior resistance, turbulence occurs just posterior to the constriction, increasing deposition in this region. To achieve a better distribution to larger and more posterior parts of the nasal mucosa, it is envisaged to be advantageous to have the drug released at a lower flow in a congested nose and at a higher flow in an open nose. This requires a system which can be released not only by flow, but also by pressure. Such release is essential for efficient and reliable exhalation-triggered nasal drug delivery. The two main triggering modes, flow and pressure, are to certain extent overlapping. They can be incorporated in one single mechanism or provided as separate mechanisms. However, the nose may become completely blocked, in particular during colds and allergic attacks. In this situation, it becomes impossible to establish a bi-directional air flow, but still it is desirable and necessary to deliver drugs to the nose.
In one aspect the present invention provides a nasal delivery device for delivering a substance to a nasal cavity of a subject, comprising: a nosepiece for fitting to a nostril of a subject; a mouthpiece through which the subject in use exhales; a nozzle for directing a substance through the nosepiece; a mechanical delivery pump fluidly connected to the nozzle for delivering a substance to the nozzle; and an actuation mechanism for actuating the mechanical delivery pump in response to oral exhalation through the mouthpiece.
In one embodiment the actuation mechanism includes a trigger mechanism for actuating the delivery pump at a predeterminable pressure.
In another embodiment the actuation mechanism includes a trigger mechanism for actuating the delivery pump at a predeterminable flow rate.
In a further embodiment the actuation mechanism includes a trigger mechanism for actuating the delivery pump at one or both of a predeterminable pressure and a predeterminable flow rate.
In one embodiment the delivery device further comprises: a flow channel fluidly connecting the nosepiece and the mouthpiece, whereby exhaled air from an exhalation breath is in use delivered through the nosepiece.
In another embodiment the delivery device further comprises: a flow channel fluidly connected to the nosepiece through which a gas flow, separate to an exhaled air flow from an exhalation breath of the subject, is in use delivered; and a gas supply unit for supplying a gas flow to the flow channel.
Preferably, the gas supply unit is configured to be actuated by exhalation through the mouthpiece.
In one embodiment the delivery pump comprises a liquid delivery pump for delivering a metered volume of a liquid.
In another embodiment the delivery pump comprises a powder delivery pump for delivering a metered amount of a powder.
In one embodiment the nozzle is configured to deliver an aerosol.
In another embodiment the nozzle is configured to deliver a jet.
In another aspect the present invention provides an oral exhalation breath-actuated mechanical nasal delivery pump unit for delivering a substance to a nasal cavity of a subject, the pump unit including an outlet nozzle and a mechanical delivery pump.
In one embodiment the delivery pump comprises a liquid delivery pump for delivering a metered volume of a liquid.
In another embodiment the delivery pump comprises a powder delivery pump for delivering a metered amount of a powder.
In one embodiment the nozzle is configured to deliver an aerosol.
In another embodiment the nozzle is configured to deliver a jet.
In a further aspect the present invention provides a method of delivering a substance to a nasal cavity of a subject, comprising the steps of: providing a nasal delivery device to the nasal cavity of a subject, the delivery device including a nosepiece for fitting to a nostril of the subject, a mouthpiece through which the subject exhales, a nozzle for directing a substance through the nosepiece, and a mechanical delivery pump fluidly connected to the nozzle for delivering a substance to the nozzle; and actuating the delivery pump in response to oral exhalation through the mouthpiece to deliver a substance through the nosepiece.
In one embodiment the step of actuating the delivery pump comprises the step of: actuating the delivery pump in response to oral exhalation through the mouthpiece on generation of a predeterminable pressure at the nosepiece.
In another embodiment the step of actuating the delivery pump comprises the step of: actuating the delivery pump in response to oral exhalation through the mouthpiece on generation of a predeterminable flow rate through the nosepiece.
In a further embodiment the step of actuating the delivery pump comprises the step of: actuating the delivery pump in response to oral exhalation through the mouthpiece on generation of one or both of a predeterminable pressure at or a predeterminable flow rate through the nosepiece.
In one embodiment the delivery device further comprises a flow channel fluidly connecting the nosepiece and the mouthpiece, whereby exhaled air from an exhalation breath is delivered through the nosepiece.
In another embodiment the method further comprises the step of: delivering a gas flow, separate to an exhaled air flow from an exhalation breath of the subject, through the nosepiece.
In one embodiment the delivery pump comprises a liquid delivery pump for delivering a metered volume of a liquid.
In another embodiment the delivery pump comprises a powder delivery pump for delivering a metered amount of a powder.
In one embodiment the substance is delivered as an aerosol.
In another embodiment the substance is delivered as a jet.
In a yet further aspect the present invention provides a method of delivering a substance to a nasal cavity of a subject, comprising the step of actuating a mechanical nasal delivery pump unit, the pump unit including an outlet nozzle and a mechanical delivery pump fluidly connected thereto, on oral exhalation by the subject to deliver a substance to a nasal cavity of the subject.
In one embodiment the delivery pump comprises a liquid delivery pump for delivering a metered volume of a liquid.
In another embodiment the delivery pump comprises a powder delivery pump for delivering a metered amount of a powder.
In one embodiment the substance is delivered as an aerosol.
In another embodiment the substance is delivered as a jet.
In a still further aspect the present invention provides an exhalation breath-actuated nasal delivery device for delivering a substance to a nasal cavity of a subject, comprising: a nosepiece for fitting to a nostril of a subject; a mouthpiece through which the subject in use exhales; a nebulizer for delivering an aerosol including a substance to the nosepiece; and an actuation unit for actuating the nebulizer when at least one or both of the pressure at or the flow rate through the nosepiece exceeds a predetermined threshold in response to oral exhalation through the mouthpiece.
In one embodiment the delivery device further comprises: a flow channel fluidly connecting the nosepiece and the mouthpiece, whereby exhaled air from an exhalation breath is in use delivered through the nosepiece.
Preferably, the actuation unit includes a flow regulator for regulating a flow of exhaled air from an exhalation breath.
In another embodiment the delivery device further comprises: a flow channel fluidly connected to the nosepiece through which a gas flow, separate to an exhaled air flow from an exhalation breath of the subject, is in use delivered; and a gas supply unit for supplying a gas flow to the flow channel.
Preferably, the gas supply unit is configured to be actuated by exhalation through the mouthpiece.
In one embodiment the nebulizer comprises an ultrasonic nebulizer.
In another embodiment the nebulizer comprises a flow-generated nebulizer.
In a further embodiment the nebulizer comprises an electrohydrodynamic nebulizer.
In yet another aspect the present invention provides a breath-actuated nasal delivery device, comprising: a flow channel including a mouthpiece through which a subject in use exhales and a nosepiece for fitting to one nostril of the subject and through which an exhaled air flow is in use delivered to the nostril of the subject; a nebulizer for delivering an aerosol including a substance to the flow channel; and a trigger mechanism for actuating the nebulizer when the pressure and/or flow of the air exhaled through the mouthpiece exceeds a predeterminable threshold.
In a still yet further aspect the present invention provides a method of delivering a substance to a nasal cavity of a subject, comprising the steps of: providing a nasal delivery device comprising a nosepiece for fitting to a nostril of a subject, a mouthpiece through which the subject exhales, and a nebulizer for delivering an aerosol including a substance to the nosepiece; and actuating the nebulizer when at least one or both of the pressure at or the flow rate through the nosepiece exceeds a predetermined threshold in response to oral exhalation through the mouthpiece.
In one embodiment the delivery device further comprises a flow channel fluidly connecting the nosepiece and the mouthpiece, whereby exhaled air from an exhalation breath is delivered through the nosepiece.
Preferably, the delivery device further comprises a flow regulator for regulating a flow of exhaled air from an exhalation breath.
In another embodiment the method further comprises the step of: delivering a gas flow, separate to an exhaled air flow from an exhalation breath of the subject, through the nosepiece.
In one embodiment the nebulizer comprises an ultrasonic nebulizer.
In another embodiment the nebulizer comprises a flow-generated nebulizer.
In a further embodiment the nebulizer comprises an electrohydrodynamic nebulizer.